tbuckley/cabot-search huggingface dataset:
Travel-Associated Dengue Cases — United States, 2010–2021
Authors: Joshua M. Wong, Aidsa Rivera, Hannah R. Volkman, Brenda Torres-Velasquez, Dania M. Rodriguez, Gabriela Paz-Bailey, Laura E. Adams
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

Dengue, the leading cause of arboviral disease worldwide, can be fatal without appropriate treatment.Among 7,528 confirmed or probable travel-associated U.S. dengue cases reported during 2010-2021, one in five (1,474, 20%) was reported in 2019.This is 168% higher than the annual average number of cases reported during 2010-2018 and 2020-2021 (approximately 550 per year) and 61% higher than the 913 cases reported in 2016, the second highest year on record.The number of cases as a fraction of air traffic volume to international destinations outside North America or Europe was also highest in 2019, with 41.9 cases per million trips, compared with 21.0 per million in other years during 2010-2021.This report compares the number and characteristics of travelassociated dengue cases reported to national surveillance in the United States in 2019 with cases reported during 2010-2018 and 2020-2021.Areas with conditions suitable for dengue transmission as well as the population at risk for dengue are expected to increase, placing U.S. travelers at higher risk for infection.Health care providers should be aware that dengue is a common cause of fever in the returning traveler and be familiar with its signs and symptoms, testing, and management.Dengue vaccines are not currently recommended for U.S. travelers; therefore, persons should review areas of dengue risk and follow guidance for preventing mosquito bites.
Costs and Causes of Oncology Drug Attrition With the Example of Insulin-Like Growth Factor-1 Receptor Inhibitors
Authors: Valerie Jentzsch, Leeza Osipenko, Jack W. Scannell, John A. Hickman
Journal: JAMA Network Open (2023)

The development of oncology drugs is expensive and beset by a high attrition rate. Analysis of the costs and causes of translational failure may help to reduce attrition and permit the more appropriate use of resources to reduce mortality from cancer.To analyze the causes of failure and expenses incurred in clinical trials of novel oncology drugs, with the example of insulin-like growth factor-1 receptor (IGF-1R) inhibitors, none of which was approved for use in oncology practice.In this cross-sectional study, inhibitors of the IGF-1R and their clinical trials for use in oncology practice between January 1, 2000, and July 31, 2021, were identified by searching PubMed and ClinicalTrials.gov. A proprietary commercial database was interrogated to provide expenses incurred in these trials. If data were not available, estimates were made of expenses using mean values from the proprietary database. A search revealed studies of the effects of IGF-1R inhibitors in preclinical in vivo assays, permitting calculation of the percentage of tumor growth inhibition. Archival data on the clinical trials of IGF-1R inhibitors and proprietary estimates of their expenses were examined, together with an analysis of preclinical data on IGF-1R inhibitors obtained from the published literature.Expenses associated with research and development of IGF-1R inhibitors.Sixteen inhibitors of IGF-1R studied in 183 clinical trials were found. None of the trials, in a wide range of tumor types, showed efficacy permitting drug approval. More than 12 000 patients entered trials of IGF-1R inhibitors in oncology indications in 2003 to 2021. These trials incurred aggregate research and development expenses estimated at between $1.6 billion and $2.3 billion. Analysis of the results of preclinical in vivo assays of IGF-1R inhibitors that supported subsequent clinical investigations showed mixed activity and protocols that poorly reflected the treatment of advanced metastatic tumors in humans.Failed drug development in oncology incurs substantial expense. At an industry level, an estimated $50 billion to $60 billion is spent annually on failed oncology trials. Improved target validation and more appropriate preclinical models are required to reduce attrition, with more attention to decision-making before launching clinical trials. A more appropriate use of resources may better reduce cancer mortality.
CTLA-4 tail fusion enhances CAR-T antitumor immunity
Authors: Xiaoyu Zhou, Hanbing Cao, Shao-Yu Fang, Ryan D. Chow, Kaiyuan Tang, Medha Majety, Meizhu Bai, Matthew B. Dong, Paul A. Renauer, Xingbo Shang, Kazushi Suzuki, Andre Levchenko, Sidi Chen
Journal: Nature Immunology (2023)
Disparities in the Timing of Preoperative Hemodialysis Among Patients With End-Stage Kidney Disease
Authors: Vikram Fielding-Singh, Matthew W. Vanneman, Arden M. Morris, Glenn M. Chertow, Eugene Lin
Journal: JAMA Network Open (2023)

This cohort study evaluates the association of patient characteristics with the interval between hemodialysis and surgery among patients with end-stage kidney disease.
vamos: variable-number tandem repeats annotation using efficient motif sets
Authors: Jingwen Ren, Bida Gu, Mark J. P. Chaisson
Journal: Genome biology (2023)

Roughly 3% of the human genome is composed of variable-number tandem repeats (VNTRs): arrays of motifs at least six bases. These loci are highly polymorphic, yet current approaches that define and merge variants based on alignment breakpoints do not capture their full diversity. Here we present a method vamos: VNTR Annotation using efficient Motif Sets that instead annotates VNTR using repeat composition under different levels of motif diversity. Using vamos we estimate 7.4-16.7 alleles per locus when applied to 74 haplotype-resolved human assemblies, compared to breakpoint-based approaches that estimate 4.0-5.5 alleles per locus.
Health Care Provider Knowledge Regarding Alpha-gal Syndrome — United States, March–May 2022
Authors: Ann Carpenter, Naomi A. Drexler, David W. McCormick, Julie M. Thompson, Gilbert Kersh, Scott P. Commins, Johanna S. Salzer
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

Alpha-gal syndrome (AGS) is an emerging, tick bite-associated immunoglobulin E-mediated allergic condition characterized by a reaction to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal), which is found in mammalian meat and products derived from mammals, including milk, other dairy products, and some pharmaceutical products. Symptoms range from mild (e.g., a rash or gastrointestinal upset) to severe (anaphylaxis); onset typically occurs ≥2 hours after exposure to alpha-gal. No treatment or cure is currently available. Despite the potential life-threating reactions associated with AGS, most patients perceive that health care providers (HCPs) have little or no knowledge of AGS. A U.S. web-based survey of 1,500 HCPs revealed limited knowledge of AGS, identified areas for continuing medical education, and described self-reported diagnostic and management practices. Overall, 42% of surveyed HCPs had never heard of AGS, and among those who had, fewer than one third knew how to diagnose the condition. Two thirds of respondents indicated that guidelines for the diagnosis and management of AGS would be useful clinical resources. Limited awareness and knowledge of AGS among HCPs likely contributes to underdiagnosis of this condition and inadequate patient management, and underestimates of the number of AGS patients in the United States, which currently relies on laboratory testing data alone.
Landscape of mSWI/SNF chromatin remodeling complex perturbations in neurodevelopmental disorders
Authors: Alfredo M. Valencia, Akshay Sankar, Pleuntje J. van der Sluijs, F. Kyle Satterstrom, Jack Fu, Michael E. Talkowski, Samantha A. Schrier Vergano, Gijs W. E. Santen, Cigall Kadoch
Journal: Nature Genetics (2023)

DNA sequencing-based studies of neurodevelopmental disorders (NDDs) have identified a wide range of genetic determinants. However, a comprehensive analysis of these data, in aggregate, has not to date been performed. Here, we find that genes encoding the mammalian SWI/SNF (mSWI/SNF or BAF) family of ATP-dependent chromatin remodeling protein complexes harbor the greatest number of de novo missense and protein-truncating variants among nuclear protein complexes. Non-truncating NDD-associated protein variants predominantly disrupt the cBAF subcomplex and cluster in four key structural regions associated with high disease severity, including mSWI/SNF-nucleosome interfaces, the ATPase-core ARID-armadillo repeat (ARM) module insertion site, the Arp module and DNA-binding domains. Although over 70% of the residues perturbed in NDDs overlap with those mutated in cancer, ~60% of amino acid changes are NDD-specific. These findings provide a foundation to functionally group variants and link complex aberrancies to phenotypic severity, serving as a resource for the chromatin, clinical genetics and neurodevelopment communities.
Addition of heparin binding sites strongly increases the bone forming capabilities of BMP9 in vivo
Authors: Claudia Siverino, Shorouk Fahmy-Garcia, Viktoria Niklaus, Nicole Kops, Laura Dolcini, Massimiliano Maraglino Misciagna, Yanto Ridwan, Eric Farrell, Gerjo J.V.M. van Osch, Joachim Nickel
Journal: Bioactive Materials (2023)

Bone Morphogenetic proteins (BMPs) like BMP2 and BMP7 have shown great potential in the treatment of severe bone defects. In recent in vitro studies, BMP9 revealed the highest osteogenic potential compared to other BMPs, possibly due to its unique signaling pathways that differs from other osteogenic BMPs. However, in vivo the bone forming capacity of BMP9-adsorbed scaffolds is not superior to BMP2 or BMP7. In silico analysis of the BMP9 protein sequence revealed that BMP9, in contrast to other osteogenic BMPs such as BMP2, completely lacks so-called heparin binding motifs that enable extracellular matrix (ECM) interactions which in general might be essential for the BMPs' osteogenic function. Therefore, we genetically engineered a new BMP9 variant by adding BMP2-derived heparin binding motifs to the N-terminal segment of BMP9's mature part. The resulting protein (BMP9 HB) showed higher heparin binding affinity than BMP2, similar osteogenic activity in vitro and comparable binding affinities to BMPR-II and ALK1 compared to BMP9. However, remarkable differences were observed when BMP9 HB was adsorbed to collagen scaffolds and implanted subcutaneously in the dorsum of rats, showing a consistent and significant increase in bone volume and density compared to BMP2 and BMP9. Even at 10-fold lower BMP9 HB doses bone tissue formation was observed. This innovative approach of significantly enhancing the osteogenic properties of BMP9 simply by addition of ECM binding motifs, could constitute a valuable replacement to the commonly used BMPs. The possibility to use lower protein doses demonstrates BMP9 HB's high translational potential.
Comparison of Calculations of the Financial Impact of Fellowship Training by Data Source
Authors: Gary L. Freed, Kyle Wickham
Journal: JAMA Network Open (2023)

Previous comparisons of potential lifetime earnings between general pediatricians and pediatric subspecialties have demonstrated that many subspecialties have lower potential lifetime earnings than general pediatrics. However, those studies selectively used specific data sources for different portions of analyses.To assess the presence and magnitude of differences in earning forecasts using different authoritative data sources.This quality improvement study analyzed compensation data for 14 pediatric subspecialties and general pediatrics from the Association of Administrators in Academic Pediatrics (AAAP), Association of American Medical Colleges (AAMC), and Medical Group Management Association (MGMA) for the 2021 to 2022 academic year.The potential lifetime compensation was calculated using the net present value (NPV), which accounts both for compensation throughout training (residency and fellowship) and compensation after graduation. The potential lifetime compensation for the subspecialties and general pediatrics was compared separately for each data source.This study included data from 3 sources about 14 subspecialties and general pediatrics. Depending on the data source, the magnitude of the difference in lifetime earnings between subspecialties and general pediatrics varied greatly. For all sources, there was a greater difference in lifetime earnings between higher- and lower-paid subspecialties compared with each other relative to general pediatrics. For the AAAP, the subspecialty with the greatest lifetime NPV is neonatal medicine, and the subspecialty with the least lifetime NPV is endocrinology, with a difference of $2 787 539. For the AAMC, cardiology has the greatest lifetime NPV and endocrinology the least, with a difference of $3 557 492. For the MGMA, neonatal medicine has the greatest lifetime NPV and adolescent medicine the least, with a difference of $4 210 477. Additionally, there is a notable difference in lifetime earnings in private vs academic practice.These findings suggest that the difference in lifetime compensation between many pediatric subspecialties and general pediatrics is not as large as previously reported. Also, greater differences exist when comparing private practice vs academic medicine and between higher- and lower-paid subspecialties.
A Population of Tumor-Infiltrating CD4+ T Cells Co-Expressing CD38 and CD39 Is Associated with Checkpoint Inhibitor Resistance
Authors: Ankita Mitra, Brian Thompson, Ann Strange, Carol M. Amato, Melinda Vassallo, Igor Dolgalev, Jonathan Hester-McCullough, Tomoaki Muramatsu, Diana Kimono, Amrutesh S. Puranik, Jeffrey S. Weber, David Woods
Journal: Clinical Cancer Research (2023)

Abstract Purpose: We previously showed that elevated frequencies of peripheral blood CD3+CD4+CD127−GARP−CD38+CD39+ T cells were associated with checkpoint immunotherapy resistance in patients with metastatic melanoma. In the present study, we sought to further investigate this population of ectoenzyme-expressing T cells (Teee). Experimental Design: Teee derived from the peripheral blood of patients with metastatic melanoma were evaluated by bulk RNA-sequencing (RNA-seq) and flow cytometry. The presence of Teee in the tumor microenvironment was assessed using publically available single-cell RNA-seq datasets of melanoma, lung, and bladder cancers along with multispectral immunofluorescent imaging of melanoma patient formalin-fixed, paraffin-embedded specimens. Suppressive function of Teee was determined by an in vitro autologous suppression assay. Results: Teee had phenotypes associated with proliferation, apoptosis, exhaustion, and high expression of inhibitory molecules. Cells with a Teee gene signature were present in tumors of patients with melanoma, lung, and bladder cancers. CD4+ T cells co-expressing CD38 and CD39 in the tumor microenvironment were preferentially associated with Ki67− CD8+ T cells. Co-culture of patient Teee with autologous T cells resulted in decreased proliferation of target T cells. High baseline intratumoral frequencies of Teee were associated with checkpoint immunotherapy resistance and poor overall survival in patients with metastatic melanoma. Conclusions: These results demonstrate that a novel population of CD4+ T cells co-expressing CD38 and CD39 is found both in the peripheral blood and tumor of patients with melanoma and is associated with checkpoint immunotherapy resistance.
Correction: Direct assessment of microcirculation in shock: a randomized-controlled multicenter study
Authors: Raphael Romano Bruno, Jakob Wollborn, Karl Fengler, Moritz Flick, Christian Wunder, Sebastian Allgäuer, Holger Thiele, Mara Schemmelmann, Johanna Hornemann, Helene Mathilde Emilie Moecke, Filiz Demirtas, Lina Palici, Marcus Franz, Bernd Saugel, Eduardo Kattan, Daniel De Backer, Jan Bakker, Glenn Hernandez, Malte Kelm, Christian Jung
Journal: Intensive Care Medicine (2023)
Use of endoscopic submucosal dissection or full-thickness resection device to treat residual colorectal neoplasia after endoscopic resection: a multicenter historical cohort study
Authors: Clara Yzet, Yann Le Baleur, Jérémie Albouys, Jérémie Jacques, Paul Doumbe-Mandengue, Maximilien Barret, Einas Abou Ali, Marion Schaefer, Jean-Baptiste Chevaux, Sarah Leblanc, Vincent Lepillez, Jocelyn Privat, Thibault Degand, Timothée Wallenhorst, Jérôme Rivory, Ulriikka Chaput, Arthur Berger, Karim Aziz, Gabriel Rahmi, Emmanuel Coron, Eric Kull, Ludovic Caillo, Geoffroy Vanbiervliet, Stéphane Koch, Fabien Subtil, Mathieu Pioche
Journal: Endoscopy (2023)

INTRODUCTION : Residual colorectal neoplasia (RCN) after previous endoscopic mucosal resection is a frequent challenge. Different management techniques are feasible including endoscopic full-thickness resection using the full-thickness resection device (FTRD) system and endoscopic submucosal dissection (ESD). We aimed to compare the efficacy and safety of these two techniques for the treatment of such lesions. METHODS : All consecutive patients with RCN treated either using the FTRD or by ESD were retrospectively included in this multicenter study. The primary outcome was the R0 resection rate, defined as an en bloc resection with histologically tumor-free lateral and deep margins. RESULTS : 275 patients (median age 70 years; 160 men) who underwent 177 ESD and 98 FTRD procedures for RCN were included. R0 resection was achieved in 83.3 % and 77.6 % for ESD and FTRD, respectively (P = 0.25). Lesions treated by ESD were however larger than those treated by FTRD (P < 0.001). The R0 rates for lesions of 20-30 mm were 83.9 % and 57.1 % in the ESD and FTRD groups, respectively, and for lesions of 30-40 mm were 93.6 % and 33.3 %, respectively. On multivariable analysis, ESD procedures were associated with statistically higher en bloc and R0 resection rates after adjustment for lesion size (P = 0.02 and P < 0.001, respectively). The adverse event rate was higher in the ESD group (16.3 % vs. 5.1 %), mostly owing to intraoperative perforations. CONCLUSION: ESD is effective in achieving R0 resection for RCN whatever the size and location of the lesions. When residual lesions are smaller than 20 mm, the FTRD is an effective alternative.
Role of nonneoplastic PVT in the natural history of patients with cirrhosis and first diagnosis of HCC
Authors: Marco Senzolo, Sarah Shalaby, Marco Grasso, Alessandro Vitale, Enrico Pizzirani, Giulio Barbiero, Alberto Zanetto, Paolo Feltracco, Paolo Simioni, Patrizia Burra, Umberto Cillo
Journal: Hepatology (2023)

Background and Aims: HCC can increase the risk of nonneoplastic PVT in cirrhosis. However, the natural history of PVT and its prognostic role in HCC patients are unknown. Approach and Results: Consecutive HCC patients with cirrhosis undergoing laparoscopic ablation were retrospectively evaluated and followed up to 36 months. HCC and PVT characteristics and evolution were reviewed. PVT was categorized according to lumen occupancy (≤50%, &gt;50% &lt;100%, and = 100%) and extension to other veins. The evolution of thrombosis was considered at 1 year from diagnosis. Variables associated with the presence of PVT and evolution patterns were analyzed, as well as their impact on survival. In all, 750 patients were included, 88 of whom had PVT. On multivariate analysis, the occurrence of PVT at HCC diagnosis was associated with pretreatment total tumor volume ( p &lt; 0.001) and clinically significant portal hypertension ( p = 0.005). During the follow-up, 46 de novo PVT occurred, 27/46 (58.7%) in the presence of a viable tumor. Among 115 PVT diagnosed in the presence of HCC, 83 had available radiological follow-up, and 22 were anticoagulated. The “complete/progressive” evolution pattern was associated with nonresponse to HCC treatment in non-anticoagulated patients. The presence of PVT was independently associated with lower overall survival, particularly when progressive or occlusive ( p &lt; 0.001). A higher competing risk of death emerged for “complete and progressive” PVT, both for HCC-related ( p &lt; 0.001) and non-HCC–related ( p = 0.002) death. Conclusions: HCC represents an independent risk factor for the occurrence and progression of PVT in cirrhosis. Since progressive and occlusive PVT seems to be an independent factor associated with mortality, screening and prompt treatment of this complication should be considered.
Zwitterionic Granular Hydrogel for Cartilage Tissue Engineering
Authors: Maryam Asadikorayem, František Surman, Patrick Weber, Daniel Weber, Marcy Zenobi‐Wong
Journal: Advanced Healthcare Materials (2023)

Abstract Zwitterionic hydrogels have high potential for cartilage tissue engineering due to their ultra‐hydrophilicity, nonimmunogenicity, and superior antifouling properties. However, their application in this field has been limited so far, due to the lack of injectable zwitterionic hydrogels that allow for encapsulation of cells in a biocompatible manner. Herein, a novel strategy is developed to engineer cartilage employing zwitterionic granular hydrogels that are injectable, self‐healing, in situ crosslinkable and allow for direct encapsulation of cells with biocompatibility. The granular hydrogel is produced by mechanical fragmentation of bulk photocrosslinked hydrogels made of zwitterionic carboxybetaine acrylamide (CBAA), or a mixture of CBAA and zwitterionic sulfobetaine methacrylate (SBMA). The produced microgels are enzymatically crosslinkable using horseradish peroxidase, to quickly stabilize the construct, resulting in a microporous hydrogel. Encapsulated human primary chondrocytes are highly viable and able to proliferate, migrate, and produce cartilaginous extracellular matrix (ECM) in the zwitterionic granular hydrogel. It is also shown that by increasing hydrogel porosity and incorporation of SBMA, cell proliferation and ECM secretion are further improved. This strategy is a simple and scalable method, which has high potential for expanding the versatility and application of zwitterionic hydrogels for diverse tissue engineering applications.